The morbidity and mortality of acute myocardial infarction remains dramatically elevated in elderly patients despite successful reperfusion treatments. The functional recovery of ischemic-reperfused tissue is impaired in elderly patients. We utilized Fischer 344 rat model of aging to study the increased injury present in the aging heart. Tissue damage was increased, and hemodynamic recovery decreased, in isolated buffer perfused hearts from 24 month elderly rats compared to 6 month adult controls. Elderly rats have a preexisting aging-related decrease in complex III and cytochrome oxidase activities that are selective to the interfibrillar population of cardiac mitochondria (IFM). Ischemia caused damage to complex III in IFM that was superimposed upon the aging defect. We propose that the baseline aging defects present in IFM act in concert with superimposed ischemic damage to augment oxidative injury during reperfusion, and that increased oxidative damage contributes to the excess injury observed in the aging heart. Oxidative reactions with mitochondrial membrane lipids will deplete cardiolipin, a phospholipid highly enriched in polyunsaturated acyl-residues, and alter the composition of cardiolipin as a signature of oxidative injury. To investigate the contributions of oxidative mechanisms to the excess injury that occurs during ischemia and reperfusion in the aging heart, we will determine if treatment with cell- permeable antioxidants such as N-2-mercaptopropionylglycine will ameliorate the excess damage observed in the aging heart during reperfusion. The targets of oxidative reperfusion injury in the aging heart in mitochondria will be assessed by measuring specific endpoints of oxidative damage including the depletion and oxidative alteration of cardiolipin. The decreased tolerance of the aging heart to ischemia and reperfusion represent a novel situation in which to explore the contributions of aging-related metabolic defects acting in concert with the superimposed metabolic stress of ischemia to further impair recovery of the aging heart. This experimental approach will delineate the targets of oxidative injury during ischemia and reperfusion in the aging heart and contribute to the design of mechanism-based adjunctive treatment strategies to enhance outcome in the high-risk elderly patient suffering from acute myocardial infarction.